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Correlation of Hsp70 Serum Levels with Gross Tumor Volume and Composition of Lymphocyte Subpopulations in Patients with Squamous Cell and Adeno Non-Small Cell Lung Cancer

View Article: PubMed Central

ABSTRACT

Heat-shock protein 70 (Hsp70) is frequently found on the plasma membrane of a large number of malignant tumors including non-small cell lung cancer (NSCLC) and gets released into the blood circulation in lipid vesicles. On the one hand, a membrane (m)Hsp70-positive phenotype correlates with a high aggressiveness of the tumor; on the other hand, mHsp70 serves as a target for natural killer (NK) cells that had been pre-stimulated with Hsp70-peptide TKD plus low-dose interleukin-2 (TKD/IL-2). Following activation, NK cells show an up-regulated expression of activatory C-type lectin receptors, such as CD94/NKG2C, NKG2D, and natural cytotoxicity receptors (NCRs; NKp44, NKp46, and NKp30) and thereby gain the capacity to kill mHsp70-positive tumor cells. With respect to these results, the efficacy of ex vivo TKD/IL-2 stimulated, autologous NK cells is currently tested in a proof-of-concept phase II clinical trial in patients with squamous cell NSCLC after radiochemotherapy (RCT) at the TUM. Inclusion criteria are histological proven, non-resectable NSCLC in stage IIIA/IIIB, clinical responses to RCT and a mHsp70-positive tumor phenotype. The mHsp70 status is determined in the serum of patients using the lipHsp70 ELISA test, which enables the quantification of liposomal and free Hsp70. Squamous cell and adeno NSCLC patients had significantly higher serum Hsp70 levels than healthy controls. A significant correlation of serum Hsp70 levels with the gross tumor volume was shown for adeno and squamous cell NSCLC. However, significantly elevated ratios of activated CD69+/CD94+ NK cells that are associated with low serum Hsp70 levels were observed only in patients with squamous cell lung cancer. These data might provide a first hint that squamous cell NSCLC is more immunogenic than adeno NSCLC.

No MeSH data available.


Related in: MedlinePlus

Hsp70 serum levels and gross tumor volume (GTV) in NSCLC patients. According to their median Hsp70 levels, NSCLC patients (n = 55; patient collective #2) were divided into patients with low GTV (≤143.6 ml; median GTV: 109.40 ml; 95th percentile: 296.30 ml) and high GTV (>143.6 ml; median GTV: 163.50 ml; 95th percentile: 688.00 ml); *p < 0.05 (Mann–Whitney U-test).
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Figure 2: Hsp70 serum levels and gross tumor volume (GTV) in NSCLC patients. According to their median Hsp70 levels, NSCLC patients (n = 55; patient collective #2) were divided into patients with low GTV (≤143.6 ml; median GTV: 109.40 ml; 95th percentile: 296.30 ml) and high GTV (>143.6 ml; median GTV: 163.50 ml; 95th percentile: 688.00 ml); *p < 0.05 (Mann–Whitney U-test).

Mentions: A comparison of free and lipid-bound Hsp70 in the circulation of tumor patients revealed that a major part of Hsp70 is bound to lipid vesicles, most likely exosomes, which are actively secreted by viable tumor cells carrying Hsp70 on their cell surface (12, 23). Therefore, we studied a potential correlation of the detected serum Hsp70 levels with the GTV of 55 NSCLC patients (patient collective #2; Table 2) that was determined by PET-imaging before start of RCT. The average tumor size of these patients was 219.9 ± 32.3 ml and the mean Hsp70 level was 11.2 ± 1.7 ng/ml. The Spearman’s Rank Correlation Coefficient revealed a significant correlation (p = 0.03) between these two metric parameters. Regarding the median GTV of 143.6 ml, these patients were subdivided into a group with low (≤143.6 ml) and high (>143.6 ml) median GTV. As shown in Figure 2, patients in the high GTV group had significantly higher serum Hsp70 levels than patients with a low tumor volume (p < 0.05).


Correlation of Hsp70 Serum Levels with Gross Tumor Volume and Composition of Lymphocyte Subpopulations in Patients with Squamous Cell and Adeno Non-Small Cell Lung Cancer
Hsp70 serum levels and gross tumor volume (GTV) in NSCLC patients. According to their median Hsp70 levels, NSCLC patients (n = 55; patient collective #2) were divided into patients with low GTV (≤143.6 ml; median GTV: 109.40 ml; 95th percentile: 296.30 ml) and high GTV (>143.6 ml; median GTV: 163.50 ml; 95th percentile: 688.00 ml); *p < 0.05 (Mann–Whitney U-test).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4629690&req=5

Figure 2: Hsp70 serum levels and gross tumor volume (GTV) in NSCLC patients. According to their median Hsp70 levels, NSCLC patients (n = 55; patient collective #2) were divided into patients with low GTV (≤143.6 ml; median GTV: 109.40 ml; 95th percentile: 296.30 ml) and high GTV (>143.6 ml; median GTV: 163.50 ml; 95th percentile: 688.00 ml); *p < 0.05 (Mann–Whitney U-test).
Mentions: A comparison of free and lipid-bound Hsp70 in the circulation of tumor patients revealed that a major part of Hsp70 is bound to lipid vesicles, most likely exosomes, which are actively secreted by viable tumor cells carrying Hsp70 on their cell surface (12, 23). Therefore, we studied a potential correlation of the detected serum Hsp70 levels with the GTV of 55 NSCLC patients (patient collective #2; Table 2) that was determined by PET-imaging before start of RCT. The average tumor size of these patients was 219.9 ± 32.3 ml and the mean Hsp70 level was 11.2 ± 1.7 ng/ml. The Spearman’s Rank Correlation Coefficient revealed a significant correlation (p = 0.03) between these two metric parameters. Regarding the median GTV of 143.6 ml, these patients were subdivided into a group with low (≤143.6 ml) and high (>143.6 ml) median GTV. As shown in Figure 2, patients in the high GTV group had significantly higher serum Hsp70 levels than patients with a low tumor volume (p < 0.05).

View Article: PubMed Central

ABSTRACT

Heat-shock protein 70 (Hsp70) is frequently found on the plasma membrane of a large number of malignant tumors including non-small cell lung cancer (NSCLC) and gets released into the blood circulation in lipid vesicles. On the one hand, a membrane (m)Hsp70-positive phenotype correlates with a high aggressiveness of the tumor; on the other hand, mHsp70 serves as a target for natural killer (NK) cells that had been pre-stimulated with Hsp70-peptide TKD plus low-dose interleukin-2 (TKD/IL-2). Following activation, NK cells show an up-regulated expression of activatory C-type lectin receptors, such as CD94/NKG2C, NKG2D, and natural cytotoxicity receptors (NCRs; NKp44, NKp46, and NKp30) and thereby gain the capacity to kill mHsp70-positive tumor cells. With respect to these results, the efficacy of ex vivo TKD/IL-2 stimulated, autologous NK cells is currently tested in a proof-of-concept phase II clinical trial in patients with squamous cell NSCLC after radiochemotherapy (RCT) at the TUM. Inclusion criteria are histological proven, non-resectable NSCLC in stage IIIA/IIIB, clinical responses to RCT and a mHsp70-positive tumor phenotype. The mHsp70 status is determined in the serum of patients using the lipHsp70 ELISA test, which enables the quantification of liposomal and free Hsp70. Squamous cell and adeno NSCLC patients had significantly higher serum Hsp70 levels than healthy controls. A significant correlation of serum Hsp70 levels with the gross tumor volume was shown for adeno and squamous cell NSCLC. However, significantly elevated ratios of activated CD69+/CD94+ NK cells that are associated with low serum Hsp70 levels were observed only in patients with squamous cell lung cancer. These data might provide a first hint that squamous cell NSCLC is more immunogenic than adeno NSCLC.

No MeSH data available.


Related in: MedlinePlus